In the United States, myopia affects nearly 25% of the population, while in certain other developed countries the proportion of the population affected increases to 80% or more. Pathological myopia is also a leading cause of blindness. Therefore, understanding the mechanisms underlying the regulation of ocular growth is critical towards understanding how and why it goes awry in eyes that develop ametropias. Much of my work has examined the influence of ocular circadian rhythms in eye growth regulation. Understanding these influences might lead to the development of therapies that are time-dependent (chronotherapies), as has been found for other pathologies, including cancer. During the previous grant period, I have established that there is a tight link between increases in choroidal thickness and inhibition of ocular elongation. Furthermore, we found that the gaseous transmitter nitric oxide (NO) might influence the changes in choroidal thickness that in turn may influence ocular growth. NO is produced by the choroid, and inhibiting its synthesis pharmacologically prevents both the choroidal and growth responses to defocus. Choroidal NO also shows a circadian rhythm in vitro. I now propose to examine the specific role of the choroid in the visual regulation of eye growth. I propose to study three signal molecules--nitric oxide (NO), dopamine, and acetylcholine (ACh)-in relation to choroidal thickening and ocular growth. Do both dopamine and ACh influence NO and/or choroidal thickness? Is NO the mediator of the choroidal response or independent of it? And, where in the signal cascade do these molecules exert their effect? Finally, I have previously found that the phase difference between the circadian rhythm of ocular elongation and that of choroidal thickness is correlated with both the changes in choroidal thickness and ocular length. I now ask whether this phase difference is essential for lens-compensation, and, by implication, for emmetropization in general. The results from these Aims will bring us closer to understanding the signal cascade mediating changes in ocular growth. Aim 1: To determine the role of the parasympathetic and sympathetic innervation to the choroid in the choroidal and growth response. Aim 2. To determine the roles of dopamine and acetylcholine in the choroidal and growth responses and how they may influence NO production. Aim 3. To distinguish between the phase advance in the choroidal thickness rhythm and a phase-dependence of the transient choroidal responses in emmetropization. PUBLIC HEALTH RELEVANCE: Myopia is reaching epidemic proportions in Asia and pathological myopia is a leading cause of blindness. Understanding how the environment (vision) influences the signal cascade between retina and sclera to produce myopia is crucial to developing drug therapies that will ameliorate it. By the same token, understanding the roles of ocular physiological rhythms in eye growth control is crucial to determining whether these therapies might depend on time of day (chronotherapy), as has been found in other pathologies, including certain cancers.